This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The tuberculosis pathogen, M. tuberculosis, requires the ESX-1 secretion system for virulence. This system is conserved among pathogenic mycobactria, including M. marinum. Understanding the components of the ESX-1 secretion system is critical to understanding the pathogenic effect of mycobacteria on host cells. Several components of the ESX-1 secretion system have been identified, and their molecular role is under intense study. We have focused our studies on protein of the ESX-1 pathway in M. marinum, designated Mh3881c, which travels from the cytosol of the mycobacteria into the host macrophages where it exerts its destructive effects. The protein undergoes processing by a periplasmic protease prior to invading host cells, and this processing is necessary for its toxicity and the pathogen's virulence. The structure of this toxin or its homologs is unknown. Determining the structure of this protein and its complexes will be invaluable in unraveling its function, and perhaps offer clues as to how its toxicity can be circumvented by small molecule inhibitors.